Despite extensive research on the pathogenesis of PD, no effective therapy is available to halt this progressive neurodegenerative disorder. One of the major roadblocks for discovering drugs against PD is the unavailability of a true chronic persistent animal model for PD. Therefore, developing a chronic persistent animal model to study the pathogenesis of PD is of paramount importance. Based on our exciting preliminary results, here studies have been proposed from various angles to delineate if simple castration of male mice leads to PD-related nigrostriatal pathologies. First, activation of microglia and astroglia and production of proinflammatory molecules in the nigra play an important role in the pathogenesis of PD. Our studies will indicate if castration leads to the activation of glial cells and the expression of proinflammatory molecules in the nigra of male mice. Second, GDNF supports normal health and viability of dopaminergic neurons and the level of GDNF goes down in the nigra of PD patients. Therefore, we will investigate if castration decreases nigral level of GDNF. Third, it has been shown that in PD patients, nigrostriatal dopaminergic neurons and neurotransmitters disappear. Therefore, we will investigate these nigrostriatal pathologies in castrated mice. Fourth, we will test if castration leads to an impairment of locomotor activities in male mice. In summary, if this project becomes successful, castrated male C57/BL6 mice may be used as a simple toxin-free chronic persistent animal model to study PD-related nigrostriatal pathologies paving the way for easy drug screening against PD. PUBLIC HEALTH RELEVANCE: One of the major roadblocks for discovering drugs against PD is the unavailability of a true chronic persistent animal model for PD. Here we will try to describe a simple toxin-free non-transgenic chronic persistent mouse model to study PD-related pathologies paving the way for easy drug screening against PD. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page